We recently discovered a p75NTR+/CD133+ population of multipotent mesenchymal stem-cell-like cells (MPMSC) in pancreatic neuroendocrine tumors that exhibit high self-renewal capacity and differentiate into endothelial, pericytes and probably other mesenchymal cells as well as into neuronal-like cells. MPMSC appear unique as they share only some markers with mesenchymal stem cells and have features that are distinct from MSC suggestive of eliciting tissue-specific functions in islets. Our discovery raises various questions as to the nature, the regulation and functional significance of MPMSC in PNET tumorigenesis. Since the function of MSC relies in tissue repair, and tumors have been described as a wound that never heals, we propose that MPMSC become activated in their perivascular niche probably at the onset of angiogenesis in dysplastic premalignant islets and support neovascularization by differentiating into endothelial cells and pericytes as well as by producing proangiogenic factors and factors that could potentially support invasion or metastasis formation. We will test the hypothesis that while MPMSC exhibit multi-potency in normal tissue, they are steered to predominantly producing vascular cells in a tumor setting to support neovascularization and repress the formation of other mesenchymal cell types such as neurons or adipocytes. This would argue that tumors activate differentiation pathways in MPMSC that are advantageous for tumor progression but inhibitory to those that are not beneficial. To determine MPMSC fate determination in vivo, we will utilize an established genetic reporter mouse system that will enable us to trace MPMSC and their progeny in vivo in the normal scenario as well as during multi-step tumorigenesis in RipTag2 mice. To elucidate the underlying mechanisms of fate determination we will test the hypothesis that PDGFR[unreadable] and the neurotrophin receptor p75NTR are implicated in differentiation pathways of MPMSC. . PUBLIC HEALTH RELEVANCE: We propose MPMSC in tumors enhance angiogenesis and eventually metastases and thus provide therapeutic targets in cancer as a response to tissue injury. On the other hand, the potential plasticity and self-renewal capacity as well as the islet-specific properties of MPMSC offers a huge potential for clinical tissue regeneration, for example in diabetic patients.